Cross-Coupling Chemistry in Continuous Flow - New Trends in Cross-Coupling: Theory and Applications - page 640

step. 70 This was recently overcome by using a sterically demanding and
electron-rich phosphine ligand, t BuBrettPhos, in combination with pal-
ladium metal to convert aryl triflates into aryl fluorides. 71 Cesium fluoride
was used as the fluorine source and it was found that increasing amounts of
CsF resulted in an accelerated fluorination protocol. 72 However, owing to the
insolubility of CsF, large amounts of CsF were dicult to handle in standard
batch vessels. A micro packed-bed reactor was filled with CsF and the re-
agents were directed over the fluoride bed. This allowed the process to be
accelerated significantly; full conversion could be achieved for a broad var-
iety of aryl triflates (Figure 13.32). Moreover, the use of this continuous flow
protocol allowed the CsF bed to be reused several times without a decrease
in reactivity. In addition, elevated temperatures and pressures provided
additional acceleration compared with the batch protocol and allowed the
catalyst loading to be reduced.

13.6 Conclusion and Outlook
The use of continuous flow microreactors for cross-coupling chemistry has
provided a number of advantages with regard to practicality, time eciency,
safety, scale-up potential and the use of harsh reaction conditions. Further
improvements in this field can be expected in the coming years. 73 Especially
direct functionalization of C-H bonds remains underdeveloped and can
probably benefit from the unusual reaction conditions provided by micro-
reactors. As is evident from this review, gas-liquid cross-coupling reactions
can significantly benefit from the intensified gas-liquid mass transfer
characteristics, and many opportunities can still be found in this area. From
a technology perspective, more ecient unit operations are required to fa-
cilitate multistep syntheses in flow. Moreover, increased automation of the
entire process will be necessary to run the flow synthesis without inter-
mediate handling. Success in these aspects will require an interdisciplinary
approach in which chemists, process engineers, software developers and
electrical engineers are involved. It should be noted that courses on flow
chemistry and continuous manufacturing are still rare in the curriculum of
many chemistry programs. If we want to embrace continuous flow tech-
nology, we should bring the chemists of the future into contact with its
benefits early in their education.

References
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